Over the past decade, the use of MRI to study multiple sclerosis (MS) has lead to substantial advances in understanding the disease process. Disease activity as detected by new lesions on T2-weighted images or contrast enhancing lesions on T1-weighted images have established that the level of activity seen on MRI is considerably greater than that seen clinically. Further, MRI has become an important and powerful tool for the assessment of the effect of new experimental therapies in MS. Recent work continues to focus on defining the natural history of the disease using MRI and in examining the effect of experimental treatments on disease activity as measured by MRI. Specifically, recent studies have focused on the following; 1. Defining the natural history of the MS lesion using both conventional imaging including T2 weighted measures of lesion load and post contrast images to identify active lesions as well as advanced imaging techniques including magnetization transfer imaging, proton spectroscopy and measures of t1 hypointensities. 2. Defining the level of new disease activity seen in patients who are early in the relapsing remitting course of the disease? 3. Defining the long term effect of treatment with interferon beta 1b on disease activity as measured by MRI. 4. Examination of the effect of new therapies on disease activity in MS as measured by MRI. Serial studies of patients with early,relapsing-remitting MS using contrast enhanced MRI have shown that nearly two thirds of the patients have evidence of active new lesion formation. Recent studies in the NIB have examined the evolution of the MS lesion using imaging techniques that measure tissue destruction such as lesion load on T2-weighted images or T1 hypointensities, alterations in magnetization transfer ratios and alterations seen using proton spectroscopy. Findings have demonstrated that progression of disease as measured by overall burden of disease increases during the early phase of the disease. However, only a modest correlation can be found between the frequency of acute enhancing lesions and the level of accumulated disease burden suggesting that distinct mechanisms may contribute to lesion progression. In addition, some patients showing a marked reduction in new disease activity as measured by contrast enhancing lesions continue to have progression of disease as measured by T2 lesion load or T1 hypointensities. Evaluation of the large natural history data set established in the NIB in collaboration with investigators at the University of Rome has provided new insights into the need for serial images to establish the true level of disease activity on MRI. Patients without activity on a single MRI had a high probability of having an active MRI over the next 5 months. These findings indicate that the value of a single MRI which does not show active disease provides a poor assessment of activity in an individual patient. These findings have important implication of trial design and sample size calculations for clinical trials using MRI as an outcome measure. Studies of the effect of experimental treatments on various stages of the MS lesion can provide valuable information at several levels. In addition to providing evidence that a treatment may be effective in the disease, changes in the evolution of the MS lesion on MRI during the use of an experimental treatment can help establish the mechanism involved in the pathogenesis of the lesion. Recent studies have examined the effect of an altered peptide, modeled on the sequence of an immunodominant epitope of myelin basic protein to modify disease. The results have shown that administration of the altered peptide can produce an increase in T cells reactive with MBP and a corresponding increase in disease activity on MRI. This observation provides very important support for the role of MBP or other myelin specific T cells in the pathogenesis of MS. Future studies will focus on the ability to modify this therapy in a manner that will result in down regulation of potentially pathogenic T cells. The effect of a growth factor, insulin-like growth factor (IGF) has also been studied. The use of a growth factor in the treatment of MS is attractive because of the potential for limiting oliogodendrocyte damage or to stimulate oligodendrocyte regeneration. However, studies of IGF in an experimental model also indicated that the drug reduced the acute inflammatory stage of disease. A study in a small cohort of MS patients has shown that in MS, IGF has no effect on the acute stage of lesion development. The effect of IGF on oliogodendrocyte survival or regeneration continues to be assessed. However, this study has shown that the use of MRI to measure regeneration is complicated and will require a combination of advance techniques to provide a true measure of change.